title: Immunodominant epitopes in herpes simplex virus type 2 glycoprotein D are recognized by CD4 lymphocytes from both HSV-1 and HSV-2 seropositive subjects.
abstract: In human recurrent cutaneous herpes simplex, there is a sequential infiltrate of CD4 and then CD8 lymphocytes into lesions. CD4 lymphocytes are the major producers of the key cytokine IFN-gamma in lesions. They recognize mainly structural proteins and especially glycoproteins D and B (gD and gB) when restimulated in vitro. Recent human vaccine trials using recombinant gD showed partial protection of HSV seronegative women against genital herpes disease and also, in placebo recipients, showed protection by prior HSV1 infection. In this study, we have defined immunodominant peptide epitopes recognized by 8 HSV1(+) and/or 16 HSV2(+) patients using (51)Cr-release cytotoxicity and IFN-gamma ELISPOT assays. Using a set of 39 overlapping 20-mer peptides, more than six immunodominant epitopes were defined in gD2 (two to six peptide epitopes were recognized for each subject). Further fine mapping of these responses for 4 of the 20-mers, using a panel of 9 internal 12-mers for each 20-mers, combined with MHC II typing and also direct in vitro binding assay of these peptides to individual DR molecules, showed more than one epitope per 20-mers and promiscuous binding of individual 20-mers and 12-mers to multiple DR types. All four 20-mer peptides were cross-recognized by both HSV1(+)/HSV2(-) and HSV1(-)/HSV2(+) subjects, but the sites of recognition differed within the 20-mers where their sequences were divergent. This work provides a basis for CD4 lymphocyte cross-recognition of gD2 and possibly cross-protection observed in previous clinical studies and in vaccine trials.
authors.affiliation: Centre for Virus Research, Westmead Millennium Institute, Westmead, New South Wales and University of Sydney, New South Wales, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Kim
authors.forename: Janette
authors.initials: J
authors.lastname: Taylor
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Zorka
authors.initials: Z
authors.lastname: Mikloska
authors.forename: Neil
authors.initials: N
authors.lastname: Bodsworth
authors.forename: Katerina
authors.initials: K
authors.lastname: Lagios
authors.forename: Heather
authors.initials: H
authors.lastname: Dunckley
authors.forename: Karen
authors.initials: K
authors.lastname: Byth-Wilson
authors.forename: Martine
authors.initials: M
authors.lastname: Denis
authors.forename: Robert
authors.initials: R
authors.lastname: Finlayson
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002461:Cell Line, Transformed; D002999:Clone Cells; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D006558:Herpes Genitalis / Q000453:epidemiology / Q000276:immunology* / Q000517:prevention & control; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D013283:Stomatitis, Herpetic / Q000276:immunology / Q000517:prevention & control; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D016056:Immunodominant Epitopes; D014759:Viral Envelope Proteins; C040570:glycoprotein D-herpes simplex virus type 2; C515577:glycoprotein gD, herpes simplex virus type 1